Abstract

Background

HER2 (ERBB2) transmembrane domain (TMD) mutations (V659E and G660D) have previously been identified in lung adenocarcinomas, but their frequency and clinical significance is unknown.

Methods

We prospectively analyzed 8,551 lung adenocarcinomas using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians for the purpose of making therapy decisions.

Results

We identified 15 cases (0.18%) of lung adenocarcinoma with HER2 TMD mutations at amino acid residues 659 or 660. These included 11 cases with V659D/E mutations, 2 with HER2 G660D, one with HER2 V659E/G660R, and one with a HER2 V659_660VE insertion. In comparison, HER2 kinase domain (KD) mutations, the majority of which were exon 20 insertions, were identified in 3.2% (273/8,551) of cases. 79% of patients with HER2 TMD mutations were female and of the 9 patients with known smoking history, 5 were never-smokers and 3 were light former-smokers. HER2 TMD mutations were mutually exclusive from HER2 KD mutations and other oncogenic drivers in lung adenocarcinoma. Only two cases with HER2 TMD mutations (13%) had concurrent HER2 amplification. Nuclear magnetic resonance analysis of HER2 TMD association revealed that mutations at position V659 and G660 to highly polar residues glutamic acid (E), aspartic acid (D) or arginine (R) stabilize homo- and hetero-dimerization of HER2 in the active conformation. Treatment of three patients with afatinib, a pan-HER inhibitor, resulted in ongoing clinical responses in all three cases, two harboring HER2 V659E and one with double HER2 V659E/G660R mutations (response > 14 months). HER2 TMD mutations (V659 and G660) are found in other non-NSCLC malignancies and analogous TMD mutations are also found in EGFR, HER3 and HER4.

Conclusions

This study expands the knowledge of targetable HER2 mutations in lung adenocarcinoma to the TMD and potentially other solid malignancies. CGP capable of detecting diverse HER2 alterations, including HER2 TMD mutations, should be broadly adopted to identify all patients who may benefit from HER2-targeted therapies.